Synthesis and Sar Study of Diarylpentanoid Analogues as New Anti-Inflammatory Agents

A series of ninety-seven diarylpentanoid derivatives were synthesized and evaluated for their anti-inflammatory activity through NO suppression assay using interferone gamma (IFN-gamma)/lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Twelve compounds (9, 25, 28, 43, 63, 64, 81, 83, 84, 86, 88 and 97) exhibited greater or similar NO inhibitory activity in comparison with curcumin (14.7 +/- 0.2 mu M), notably compounds 88 and 97, which demonstrated the most significant NO suppression activity with IC50 values of 4.9 +/- 0.3 mu M and 9.6 +/- 0.5 mu M, respectively. A structure-activity relationship (SAR) study revealed that the presence of a hydroxyl group in both aromatic rings is critical for bioactivity of these molecules. With the exception of the polyphenolic derivatives, low electron density in ring-A and high electron density in ring-B are important for enhancing NO inhibition. Meanwhile, pharmacophore mapping showed that hydroxyl substituents at both meta-and para-positions of ring-B could be the marker for highly active diarylpentanoid derivatives.